The present invention relates to novel aliphatic sulfamates. The sulfamates may be represented by the formula: ##STR1## wherein n is an integer from 0-8 and X and Y are hydrogen, provided that when n is 1, X and Y are hydrogen, lower alkyl having 1-3 carbon atoms, aryl such as phenyl or arylalkyl such as benzyl, phenethyl and the like, and R.sub.1 and R.sub.2 are hydrogen, alkyl having 1-7 carbon atoms, aryl, arylalkyl such as benzyl, phenethyl, phenylpropyl and the like, cycloalkyl such as cyclopentyl, cyclohexyl and the like, or R.sub.1 and R.sub.2 together with the nitrogen atom to which they are attached form a saturated heterocyclic ring. Preferred among these compounds are those compounds wherein R.sub.1 and R.sub.2 are hydrogen.
The novel aliphatic sulfamates of the present invention are prepared by reacting an alkanediol with a sulfamoyl halide in a suitable solvent in the presence of a strong base. Suitable alkanediols which may be employed include 1,2-ethanediol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,10-decanediol and the like. As the halide reactant, sulfamoyl chloride and N,N-di or mono substituted sulfamoyl halides may be employed. Bases such as sodium hydride, sodium amide, sodium hydroxide, pyridine and tributyltin are examples of suitable strong bases. Examples of solvents which may be employed include 1,2-dimethoxyethane, ether, tetrahydrofuran, diglyme and p-dioxane. The reaction with the sulfamoyl halide may be carried out at room temperature, but it is preferred to carry out the reaction at a temperature between 0.degree.-10.degree. C. The sulfamate is obtained from the reaction mixture by techniques known to those skilled in the art.
The novel aliphatic sulfamates are useful in the control of fertility in male animals. The compounds are capable of interfering with sperm as they sojourn in the epididymis and thus result in what is known as functional sterility, i.e. the gametes remain morphologically normal and show motility but normal fertilization is not achieved. Generally dosage levels of from about 5-200 mg./kg. are effective in inducing functional sterility. The preferred dosage range is from about 10-150 mg./kg. In addition to causing functional sterility of epididymal sperm, the novel sulfamates have antiandrogenic properties as manifested by inhibition of the size of the ventral prostate.
The general procedure followed to determine the activity of compounds which inhibit male fertility by altering the functional capacity of epididymal sperm is as follows:
A 2 week dosing period (i.e., the approximate period required for sperm transport through the epididymis) enables separation of those drugs which affect epididymal sperm maturation and/or function from the antispermatogenic agents which have a longer delay in the onset of sterility.
Each individual test involves 5 male rats (250-300 g.) caged together in air conditioned animal quarters and maintained on laboratory chow and tap water ad libitum. The compound to be tested is dissolved or suspended in appropriate vehicles (usually methylcellulose) and administered daily (usually i.g.) for 14 consecutive days. Control animals receive the vehicle only. At the end of the 14th day of treatment each male is individually caged with a proestrus female. Vaginal smears are checked the following morning for evidence of positive mating, and those males failing to mate are recohabited with proestrus females the following night. Males are sacrificed and autopsied the day after cohabitation for a gross examination of testes, epididymides, and accessory sex organs. Tissue samples of these organs are preserved for histological processing if observation yields a possible effect. Females (regardless of sperm presence in the vaginal washings) are autopsied 14 days after cohabitation to examine for pregnancy.
The inability of females to produce a viable embryo following a successful mating with treated males (two weeks of medication) is used as a measure of functional infertility. The number of males mating of those cohabited gives a gross indication of the drug's effect on libido. The size of the accessory sex organs provides an indication of the effect on androgen production. Microscopic analysis of epididymal sperm provides information on sperm quality (motility and morphology) and quantity.